Recent experiments have shown that natural killer (NK) cells play a pivotal role in the acute rejection of bone marrow transplants and that they may be involved in the regulation of hemapoiesis. In previous studies, our research involved establishing and cloning murine cell lines with NK activity, characterizing their cell surface antigen and exploring their in vitro specificity and function. We had also shown that cloned NK cells, if injected into NK-deficient beige mice, cause specific bone marrow graft rejection. The aim of this study is to examine why NK cells are able to exert specific bone marrow graft rejection in vivo. This is important because it will uncover the mechanisms by which NK cells are able to exert their immunosurveillance function in vivo. In the first part of the study, we will explore what cell types, besides NK cells, may be involved in marrow graft rejection. We will focus our attention primarily on natural cytotoxic (NC) cells and specific T cells with the aim to examine whether these cell types direct the apparently nonspecific NK cells in their specific function in vivo. Since NK cells are able to act in an antibody-dependent cell-mediated reaction, our research will explore the possibility that the in vivo specificity of NK cells is directed by humoral antibody that is naturally present in the serum of transplant recipients. Our experiments will involve both in vitro and in vivo models of bone marrow rejection in order to correlate experimental results obtained from both types of models. In order to explore the action of accessory cells in marrow graft rejection, specific antibody-complement treatment and animal models lacking certain cell types will be employed. The potential involvement of antibody will be assessed by either in vivo administration of antibody or assay of its presence in animals able to reject certain marrow grafts. This will be done by serum transfer experiments as well as by direct assay for antibodies in responder serum by using, for instance, antibody-dependent cytotoxicity (ADCC) assays. In the last part of the project, we will try to apply our findings to the B16 melanoma model system which is known to involve NK cells in tumor rejection. (TT)